10-(2-Dialkylaminoethyl)-10,11-dihydro, or 10-(2-dialkylaminoethyl)-5-methylene-2,7-substituted or unsubstituted-5H-dibenzo{8 a,d{9 cycloheptenes

ABSTRACT

10-(2-dialkylaminoethyl)-10,11-dihydro, or 10-(2dialkylaminoethyl)-5-methylene-2,7-substituted or unsubstituted5H-dibenzo(a,d)cyclo-heptenes e.g. 10-(2-dimethylaminoethyl)10,11-dihydro-5-methylene-5H -dibenzo(a,d)cycloheptene, prepared by acid dehydration the corresponding dibenzo(a,d)cycloheptene-5ols. The compounds are useful as anti-depressants.

United States Patent [191 Houlihan et al.

[ 10-(2-DIALKYLAMINOETHYL)-10,1l-

DIHYDRO, OR 10-(2-DIALKYLAMINOETHYL)-5- METHYLENE-2,7-SUBSTITUTED ORUNSUBSTITUTED-SH-DIBENZO[A,D]CY- CLOHEPTENES [75] Inventors: William J.Houlihan, Mountain Lakes,'N.J.; Jeffrey Nadelson, Lake Parsippany, NJ.

[73] Assignee: Sandoz, Inc., E. Hanover, NJ.

[22] Filed: Feb. 7, 1972 2 i1 Appl. No.: 224,323

[44] Published under the Trial Voluntary Protest Program on January 28,1975 as document no. B 224,323.

[52] US. Cl. ..260/570.8 TC; 260/343.2 R; 260/501.1;260/50l.21; 260/518R;

260/518 A; 260/519; 260/558 A; 260/558 D; 260/570.5 C; 424/316; 424/330[51] Int. Cl. C07C 87/29 [58] Field of Search 260/501.1, 501.2, 570.8 TC

[56] References Cited UNITED STATES PATENTS 3,409,640 11/1968 Villani..260/570.8

[451 Dec. 9, 1975 3,649,692 3/1972 Humber 260/570.9

OTHER PUBLICATIONS Russel, Chemical Abstracts, Vol. 71, p. 323, No.10l6l1w (1969).

Chemical Reviews, Vol. 64, No. 3, pp. 243-244 and 246-247 (1964).

Cope et al., Journal American Chemical Society, Vol. 73, pp. 1674-1675and 1677 (1951).

Primary ExaminerRobert V. Hines Attorney, Agent, or Firm-Gerald D.Sharkin; Robert S. Honar [57] ABSTRACT 3 Claims, N0 Drawings10-(2-DIALKYLAMlNOETHYL)-10,1 l-DIHYDRO, R

OR 10-(Z-DIALKYLAMINOETHYL)-5-METHYLENE- 2,7-SUBSTITUTED OR 7 YUNSUBSTITUTED-5H-DIBENZO[A,D]CYCLOHEP:

TENES This invention relates to S-methylene-SH-dibenlzo[a,d]cycloheptenesi More particularly, it relates to 2lO-(2-dialkylaminoethyl)-l0, ll-dihydro, or -(2- 0dialkylaminoethyl)-5-methylene-2,7-substituted orunsubstituted-5H-dibenzo[a,d]cycloheptenes, acid addition salts thereof,intermediates thereof, and processes for their preparation.

The compounds of this invention may be represented l 5 by the followingstructural formula:

NCH CH lowing reaction scheme A:

NCH CH 2 2 R R 1 acid dehydration *9 R (II) (Ia) wherein wherein R R Rand R have the above stated signifi' R and R are independently hydrogen,lower alkyl cance.

having 1 to 3 carbon atoms, e.g. methyl, ethyl, pro- The compounds offormula (Ia) may be prepared by pyl, or isopropyl, lower alkoxy having 1to 3 carbon treating a compound of formula (II) in an acid dehyatoms,e.g. methoxy, ethoxy, propoxy, or isoprodration medium such as dilute orconcentrated mineral poxy, halo having an atomic weight of 19 to 36 oracids such as sulfuric acid, hydrochloric acid and the trifluoromethyl,like, in inert hydrocarbons such as benzene, toluene I and the like, ata temperature from about C to the R3 and R4 are mdependenfly lower alkylhavmg 1 to reflux temperature of the reaction medium, preferably 3Carbon atoms and the reflux temperature, for about 1 to 24-hours, prefer50 ably l to 4 hours. The preferred acid dehydration me I,

A d B b th h d A d B t th f s l gg bi iim an Oge er Orm dium is 1M to 5MSUifLlI'lC acid, Neither the solvents nor the temperatures used arecritical:

The compounds of formula (I) may also be repre- The compounds of formula(lb) maybe prepared sented by the following structural formulas: thefollowing reaction scheme B:

NCH ca R 2 2 R acid. dehydration 2 H0 CH (1n) (In) R A I adduct whereinR R R and R have the above stated signifiwherein R R R and R and M havethe above stated cance. significance.

The compounds of formula (Ib) may be prepared by The compounds offormula (III) may be prepared by treating a compound of formula (VI)with an organothe acid dehydration of a compound of formula (III),

metallic reagent of formula (V) using the solvents and using thesolvents and under the reaction conditions described in scheme A.Neither the solvents nor the under the reaction conditions described inscheme A. temperatures used are critical. The compounds of for- Neitherthe solvents nor the temperatures used are critmula (II) may be preparedby the following reaction ical. scheme C: The compounds of formula (IV)may be prepared by x02; ca NC'rZ CH R 2 2 2 2 a I; R R

MN h I l. i I ca M adduct MN 3 hydrolys i.

l 2 E, no as I (iv; I (II) wherein R R R R have the above statedsignifi- 25 the following reaction scheme E:

2 CO H R 2 4- 6 r M /R3 R CH2CH R cyclizat ion R I h U 1 2 (VII) (IV)cance, and M is Li or Mg. wherein R R R and R have the above statedsignifi The compounds of formula (II) may be prepared by cance.

treating a compound of formula (IV) with an organometallic reagent offormula (V) e.g. methyllithium, and 45 the like in the presence of aninert atmosphere e.g. ni-

gogen an g ii z Such as diethyl S acid medium such as sulfuric acidphosphoric acid t t t t t g g g ggfi 5; 15235212??? 5 polyphosphoricacld and the like at a temperature of y from 70to 150C preferably 100 to120 C for about 3 mmutes preferably to mmutes followed by Stan to 24hours, preferably about 4 to 8 hours. Neither the dard hydrolysls thereultmg afiduct 3 Water or solvents nor the temperatures used arecritical. aqueous ammonium chloride solution. Neither the solvents northe temperatures used are critical.

The compounds of formula (III) may be prepared by The compounds offormula (VI) may be prepared by the following reaction scheme D: 4 thefollowing reaction scheme F:

The compounds of formula (IV) may be prepared by cyclization of acompound of formula (VII) in a strong .NCH CII 2 hydrolysis 3 j NCH on M2 2 l cn cn n Ring I Enlargement l s R R (VIII) (vI) wherein R R R and Rhave the above stated signifiwherein cance. R R R and R are as indicatedabove, and

The compounds of formula (VI) may be prepared by ring enlargement of acompound of formula (VIII) 20 under the reaction condition as describedin scheme E.

Neither the solvents nor the temperatures used are crit- R representslower alkyl, as previously defined.

The compounds of formula (VIII) are prepared by heating a compound offormula (IX) optionally in inert ical. solvent such as tetrahydrofuran,hydrocarbons or halogenated hydrocarbons such as hexane, heptane, ben-The compounds of formula (VII) may be prepared by 25 zene, toluene,o-dichlorobenzene and the like, at about the following reaction schemeG:

o 1' co n I on (.H m R I k 2 2 h ca ca CH cii 3 k/ I R R 2 (VIII) 2(VII) The compounds of formula (VII) may be prepared by 40 60220C.preferably about l40160C. for about hydrogenating a compound of formula(VIII) in the to 48 hours, preferably about to 28 hours. The tempresenceof palladium on char al at an at h f peratures and times used are notcritical. To improve from to 100 i r f bl 50 t i, i a i t yields andobtain a better quality product, the reaction lower alkanol having 1 to4 carbon atoms, such as m y be Performed under inert atmopshere,-gnitromethanol, ethanol, propanol, isopropanol, butanol, or 45 g gisobutanol, at a temperature of from 20 to C. pref- The compounds offormulas (Ia) (lb) (H) (In) 0 O 7 7 i Q erably 2 5 to 35 C, until oneequivalent amount of hy- (IV), (VI), and (VII) may exist in the form oftheir acid P a bsorbed' To enhance, the reactlon, aqtfeous additionsalts. Said salts and their respective free bases mineral acid such ashydrochloric acid, sulfuric acid, or may be converted from one to theother by c0nven perFhbnc acld may be added to the reactlon medlum' 50tional techniques and are chemically interchangeable glelthez thlesolvents, temperatures or pressures used for purposes of the abovedescribed processes re cri 1ca The compounds of formula (VIII) may beprepared by the following reaction scheme H:

The compounds of formula (IX) may be prepared as indicated by thefollowing reaction scheme I:

wherein R R R R and R are as indicated above.

The compounds of formula (IX) are prepared by condensing a compound offormula (X) with a compound of formula (XI) in the presence of inertatmosphere, e.g. nitrogen gas, in an inert solvent such as diethylether, tetrahydrofuran, hexane, heptane, benzene and the like ormixtures thereof, and subjecting the reaction mixture of hydrolysis,preferably with aqueous ammonium chloride. The condensation may becarried out at a temperature of from about 80 to 20C., preferably 60 to40C; for about 1 to 3 hours. The hydrolysis is performed in conventionalmanner at a temperature of about 20 to C. Neither temperatures, solventsnor hydrolyzing agent used are critical. Compound (XI) is preferablyadded in inert solvent to a cold (60 to -40C.) inert solvent solution ofcompound (X).

The compounds of formula la, lb, II, III, IV, VI, VII, VIII and IX, maybe recovered using conventional recovery techniques such ascrystallization.

Certain of the compounds of formula (X) and (XI) are known and may beprepared by methods disclosed in the literature. Those compounds (X) and(XI) not specifically disclosed may be prepared by analogous methodsfrom known materials.

It will be understood that certain of the compounds of formula (VIII)exist in racemic form or in the form of optically active isomers. Theseparation and recovery of the respective isomers may be accomplishedemploying conventional techniques and such isomers are included withinthe scope of this invention.

The compounds of formulas (la) and (lb) are useful because they possesspharmacological activity in animals. More particularly, the compounds offormulas (Ia) and (lb) are useful as anti-depressant agents as indicatedby their activity in mice given intraperitoneally 0.1 to 25 mg/kg ofbody weight of active material, and tested by the method basically asdescribed by Spencer, P.S.J., Antagonism of Hypothermia in the Mouse byAnti-depressant Drugs, pp. 194-204, Ed. S. Garattini and M. N. G. Dukes,Excerpta Medica Foundation, 1967, and by their activity in the cat giventypically O.25-2.0 mg/kg of body weight of active material and testedfor their effect on -hydroxytryptophan and 1- tryptophan induced spinalmonosynaptic reflex transmission, basically as described by Anderson E.G. and Shibuya T., the Effects of S-Hydroxytryptophan and l-tryptophanon Spinal Synaptic Activity, pp. 352 to 360, .l. of Pharm. and Exp.Therapeutics, Vol. 153, No. 2, 1966.

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carriers or adjuvants. They may beadministered orally or par- 7 8 o 0 3 1. oir cii ir i I AWE R 5 9 l 1 5on ca L 1 2 1 R1 011 011 011 (X) (x1) (Ix) enterally and, depending uponthe compound employed and the mode of administration, the exact dosageutilized may vary.

Furthermore, the compounds (Ia) and (lb) may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid'additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly, are included within the scope of the invention.Representative of such salts are the mineral acid salts, such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate, maleate and the like. i

In general, satisfactory results are obtained when the compounds areadministered as anti-depressants at a daily dosage of from about 0.2 tomilligrams per kilogram of animal body weight. This daily dosage ispreferably given in divided doses, e.g., 2 to 4 times a day, or insustained release form. For most large animals, the total daily dosageis from about 15 to 600 milligrams and dosage forms suitable forinternal administration comprise from about 3.75 to 300 milligrams ofthe compound in admixture with a solid or liquid pharmaceutical carrieror diluent.

EXAMPLE 1 2-(B-[2-dimethylaminoethyl]-B-hydroxyphenethyl)-N-methylbenzamide To a flask equipped with a stirrer, dropping funnel,condenser and gas inlet tube maintained under a nitrogen atmospherethere is added at room temperature 40.0 g (0.28 mole) ofo-methyl-N-methyl benzamide and 250 ml of anhydrous tetrahydrofuran. Thereaction flask is immersed in an ice bath and cooled to an internaltemperature of 5C. Stirring is added dropwise in ca. 1 hour maintainingthe temperature below 8C. The resulting red dilithio salt (compound X)is stirred at 5C. for 1 additional hour and the reaction flask is thenimmersed in a dry-ice acetone bath and cooled to an internal temperatureof 60C. To the cold reaction mixture a solution of 49.7 g. (0.28 mole)3-dimethylaminopropiophenone in ml. anhydrous tetrahydrofuran is addeddropwise in ca. 45 min. maintaining the temperature between 60C and-50C. The resulting reaction mixture is stirred at 60C. for 1 hour,allowed to warm to 0C. in ca. 1 hour, and then treated with 200 ml. ofsaturated aqueous ammonium chloride while maintaining the temperaturebelow 10C. The resulting solid is filtered, washed thoroughly with waterand recrystallized from methylene chlorideether (1:1) to give2-(,B-[Z-dimethyIaminOethyH-B- hydroxyphenethyl)-N-methylbenzamide; m.p.139.5-140.5C.

When the above detailed process is carried out and in place ofo-methyl-N-methyl benzamide there is used a. N,2, 4-trimethylbenzamide,

b. 4-methoxy-N,Z-dimethylbenzamide,

c. 4-chloro-N,2-dimethylbenzamide,

d. o-methyl-N-methyl benzamide, or

e. 4-trifluoromethyl-N ,2-dimethylbenzamide, and in place of3-dimethylaminopropiophenone there is used,

a. 3-dimethylamino-4'-methylpropiophenone,

b. 3-dimethylamino-4 -methoxypropiophenone,

c. 4'-chloro-3-dimethylaminopropiophenone,

d. 3-diisopropylaminopropiophenone, or

e. 3-dim ethylamino-4 '-trifluromethylpropiophenone,

and combining the correspondingly lettered benzamides andpropriophenone, there is obtained.

a. 2-(4-dimethylamino-2-hydroxy-2-p-methylphenyl) butyl-N,4-dimethy1benzamide,

Z-(B-[Z-dimethylaminoethyl]-B-hydroxy-4- methoxyphenethyl)-4-methoxy-N-methylbenzamide.

c. 4-chloro-2-(4-chloro-B-[2-dimethylaminoethyl]-,B-hydroxyphenethyl)-N-methylbenzamide,

d. 2-(B-hydroxy-B-[2-diisopropylaminoethyl]phenethyl)-N-methylbenzamide,or

e.2-(B-[Z-dimethylaminoethyl]-,B-hydroxy-4-trifluoromethylphenethyl)-4-trifluoromethyl-N-methylbenzamide, respectively.

EXAMPLE 2 3-[2-dimethylaminoethyl]-3,4-dihydro-3- phenylisocoumarin To aflask equipped with a stirrer, condenser and gas inlet tube maintainedunder a nitrogen atmosphere there is added at room temperature 16.3 g(0.05mole) of Z-(B-[Z-dimethylaminoethyl]-B-hydroxyphenethyl)-N-methylbenzamide and 170 ml of o-dichloro benzene. Stirring isinitiated and the mixture is heated at reflux for 18 hours. The excesso-dichlorobenzene is then removed by distillation in vacuo and theresulting oil is crystallized from ether to give3-[2-dimethylaminoethyl]-3,4-dihydro-3-phenylisocoumarin; m.p.95.095.5C.

When the above process is carried out and in place ofZ-(B-[Z-dimethylaminoethyl]-B-hydroxyphenethyl)-N-methylbenzamide, thereis used a. 2-(4-dimethylamino-2 -hydroxy-2-p-methylphenyl) butyl-N,4-dimethylbenzamide,

2-(B- 2-dimethylaminoethyl -B-hydroxy-4-methoxyphenethyl)-4-methoxy-N-methylbenzamide,

c. 4-chloro-2-(4-chloro-B-[2-dimethylaminoethyl]-B-hydroxyphenethyl)-N-methylbenzamide,

d. 2-( B-hydroxy-B- 2-diisopropylaminoethyl]phenethyl)-N-methylbenzamide, or

rin, respectively.

EXAM PLE I 3 10-( 2-dimethylaminoethyl)- l 0,1 l-dihydro-S-methylene,5H-dibenzo [a,d] cycloheptane maleate Step A2-(B-[Z-dimethylaminoethyl]phenethyl)benzoic acid hydrochloride Asolution of 14.75 g (0.05 mole) of 3-(2-dimethylaminoethyl)-3,4-dihydro-3-pheny1isocoumarin in 150 ml ethanol containing 5 ml covnc.hydrochloric acid and lg 10% palladium on charcoal is hydrogenated at 50psi and room temperature till one equivalent of hydrogen is absorbed.The mixture is filtered and evaporated to give the intermediate2-(fi-[2-dimethylaminoethyl]phenethyl)benzoic acid hydrochloride, m.p.l53-6C. I Step B 10-(2-dimethylaminoethyl)-10,1 l-dihydro-SH-dibenzo[a,d] cyclohepten-S-one hydrochloride A mixture of 14.75 g (0.05mole) of 2-(B-[2-dimethylaminoethyl]phenethyl) benzoic acidhydrochloride and 150 g polyphosphoric acid is heated at l 10C for 6hrs. allowed to cool and poured onto crushed ice with stirring. Theresulting solution is .cooled on ice and made basic by the addition ofsolid potassium hydroxide, and extracted with methylene chloride. Themethylene chloride is washed with water, dried over anhydride magnesiumsulfate and evaporated in vacuo. The

v e.2-(B-[Z-dimethylaminoethyl]-B-hydroxy-4-trifluoromethylphenethyl)-4-trifluoromethy1-Nmethylbenzamide, there is obtained methylphenyl)-6-methylisocoumarin,

b) 3-(2-dimethylaminoethyl)-3,4-dihydro-3-(4-methoxyphenyl)-6-methoxyisocoumarin,

ethyl)-3 ,4-dihydroisocoumarin3-(2-dimethylaminoethyl)-3,4-dihydro-3-(4- residue is dissolved inisopropanol, and treated with gaseous hydrogen chloride. The resultingprecipitate is filtered and recrystallized from isopropanol to give theintermediate lO-(2-dimethylaminoethyl)-10,1 l-dihydro-5H-dibenzo [a,d]cyclohepten -5-one hydrochloride, m.p. l88190C. Step C I r10-(2-dimethylaminoethyl)-10,1 l-dihydro-S-methyl- 5H-dibenzo[a,d]cyclohepten-S-ol To a solution of 19.4 g (0.07 mole) of10-(2-dimethylaminoethyl) -l0,1 1-dihydro-5H-dibenzo[a,d]-cyclohepten-S-one in 200 ml diethylether,-under nitrogen, cooled to-5ml 1.5N methyllithium (0.105 mole) in diethylether is added dropwisewith stirring, maintaining temperature below 0, 15 minutes after theaddition is complete the reaction is quenched by the addition of 50 m1saturated ammonium chloride solution. The organic layeris separated,extracted with saturated sodium chloride solution, dried over anhydrous,magnesium sulfate and evaporated. The crystalline residue isrecrystallized from methylenechloride-methanol 1:1 to give theintermediate l0-(2 dimethylarninoethyl)-10,1 1,-dihydro-5-methy1-5H-dibenzo[a,d]cyclohepten-5-ol, 161.5-162C. Step D 10-(Z-dimethylamino ethyl l 0,1l-dihydro-S-methylene-5H-dibenzo[,a,d]cycloheptene m aleate A mixture of8g (0.027 mole) of 10-(2-dimethylaminoethyl)-10,1l-dihydro-5-methyl-5H-dibenzo[a,d]-cyclohepten-5-o1 and i 250 m12M-sulfuric acid is refluxed for 2 hrs. The mixture is cooled in ice andmade basic by the addition of solid potassium hydroxide. The mixture isextracted with methylene chloride. The methylene chloride is washed withwater, dried over anhyd. magnesium sulfate and evaporated in vacuo. Theoily residue is distilled at l40C/0.5mm and the distillate is dissolvedin ethanol and treated with maleic acid. The precipitate is filtered andrecrystallized from diethylether-ethanol 1:1 to give the product10-(2-dimethylaminoethyl)- 10,1 1dihydro-5-methylene-5H-dibenzoa,d]cycloheptene maleate, m.p. l7l172C.

EXAMPLE 4 d. -3-(2-diisopropylaminoethyl)-3,4-dihydro-3-phenylisocoumarin, e. 3-(2-dimethylaminoethyl)-3 ,4-dihydro-6-tri- Ifluoromethyl-3-(4-trifluoromethylphenyl)isocoumarin, the followingintermediates are obtained,

a. 2-( B-[2 dimethylaminoethyl]-p-methylphenethyl)- 4-methylbenzoic acidhydrochloride,

b. 2-( ,8- Z-dimethylamininoethyl -p-m ethoxyphenethyl)-4-methoxybenzoicacid hydrochloride,

0. 4-chloro-2-(B-[Z-dimethylaminoethyl]-p-chlorophenethyl)benzoic acidhydrochloride,

d. 2-(B-[2-diisopropylaminoethyl]phenethylbenzoic acid hydrochloride, or

e. 2-( ,B- 2-dimethylaminoethyl]-p-trifluoromethylphenethyl)-4-trifluoromethylbenzoic acidhydrochloride, respectively. Step B Following the procedure of Example3, step B and in place of 2-(B-[Z-dimethylaminoethyl]phenethyl)benzoicacid hydrochloride, and starting with the correspondingly letteredintermediate of step A of this example, the following intermediates areobtained,

a. l-(2-dimethylaminoethyl)-10,1 1-dihydro-2,7-dimethyl-5H-dibenzo[a,d]cyclohepten-S-one hydrochloride,

-(2-dimethylaminoethyl)-10,1 1-dihydro-2,7-dimethoxy-SH-clibenzo[a,d]cyclohepten-5-one hydrochloride, c.l0-(2-dimethylaminoethyl)-10,1 1-dihydro-2,7-

dichloro-5H-dibenzo[a,d] cyclohepten-S-one hydrochloride,

lO-( 2-diisopropylaminoethyl )-l0,1 l-dihydro-SH-dibenzo[a,d]cyclohepten- 5-one hydrochloride, or

e. 10-(2-dimethylaminoethyl)-l0,1 l-dihydro-2,7-

bis(trifluoromethyl)-5H-dibenzo[a,d]cyclohepten-S-one hydrochloride,respectively.

Step C Following the procedure of Example 3, step C and in the place of10-( 2-dimethylaminoethyl)-10,1l-dihydro-5H-dibenzo[a,d]-cyclohepten-5-one hydrochloride, and startingwith the correspondingly lettered intermediate of step B of thisExample, the following intermediates are obtained,

a. 10-(2-dimethylaminoethyl)-10,1 l-dihydro-2,5 ,7-

trimethyl-5H-dibenzo[a,d] cyclohepten-S-ol,

l0-( 2-dimethylaminoethyl)-10,1 l-dihydro-2,7- dimetho xy-5 -methy1-5H-dibenzo a,d] cyclohepten-S-ol,

c. 10-(2-dimethylaminoethyl)-10,1 1-dihydro-2,7-

dichloro-5-methyl-5H-dibenzo[a,d]cyclohepten-S-ol,

10-(2-diisopropylaminoethyl)-10, 1 1-dihydro-5- methyl-5H-dibenzo[a,d]cyclohepten ,-5-ol, or e. 10-(2-dimethylaminoethyl)-10,1l-dihydro-S- methyl-2 ,7-bis (trifluoromethyl5H-dibenzo[a,d]cyclohepten-S-ol, respectively. Step D Following theprocedure of Example 3, step D and in place of 10-(2-dimethylaminoethyl)-10,1 l-dihydro-5methyl-5l-l-dibenzo[a,d]-cyclohepten-S-ol, and starting with thecorrespondingly lettered intermediate of step C of this Example, thefollowing products are obtained,

lO-(2-dimethylaminoethyl)-10,1 l-dihydro-2,7-dimethyl-S-methylene-5H-dibenzo[a,d]cycloheptene maleate,

l0-( 2-dimethylaminoethyl)-10,1 l-dihydro-2,7- dimetho xy-S-methylen e-5H-dibenzo [a,d cycloheptene maleate. c. 10-(2-dimethylaminoethyl)-10,11-dihydro-2,7- dichloro-S-methylene-5H-dibenzo[a,d]cycloheptene maleate,

l0-(2-diisopropylaminoethyl)-10,1 l-dihydro-S-methylene5H-dibenzo[a,d]cycloheptene maleate,

or e. l0-(2-dimethylaminoethyl)-10-1 1-dihydro-2,7- bis( trifluoromethyl)-5 -methylene- SH-dibenzo[a,d]cycloheptene maleate, respectively.

EXAMPLE 5 10-( Z-dimethylaminoethyl )-5-methylene-5H-dibenzo[a,d]cycloheptene hydrochloride allowed to cool and poured ontocrushed ice with stirring. The resulting solution is cooleld in iceand'made basic by the addition of solid potassium hydroxide andextracted with methylene chloride. The methylenechloride is washed withwater, dried over anhyd. magnesium sulphate and evaporated in vacuo. Theresidue is dissolved in isopropanol, treated with gaseous hydrogenchloride. The resulting precipitate is filtered and recrystallized fromisopropanol to give the intermediate 10-(2-dimethylaminoethyl)-5H-dibenzo[a,d]cyclohepten-S-one hydrochloride, m.p. 204206C. Step B10-( Z-dimethylamino ethyl )-5 -meth yl-SH-dibenzo[a,d]cycloheptene-S-olTo a solution of 19.4 g (0.070 mole) oflO-(Z-dimethylaminoethyl)-5H-dibenzo[a,d]-cycloheptene-S-one in 200 mldiethylether under nitrogen cooled to 5C, ml of 1.5M methyllithium(0.105 mole) in diethylether is added dropwise with stirring,maintaining temperature below 0, 15 minutes after the addition iscomplete the reaction is quenched by the addition of ml saturatedammonium chloride solution. The organic layer is separated, extractedwith saturated sodium chloride solution, dried over anhyd. magnesiumsulfate and evaporated. The crystalline residue is recrystallized frommethylenechloride-diethylether to give the intermediatelO-(2-dimethylaminoethyl)-5-methyl-5H-dibenzo[a,d

cyclohepten-S-ol, m.p. l35-l36.5C. Step C Z-dimethylamino ethyl)-5-methylene-5 l-l-dibenzo[a,d]cycloheptene hydrochloride A mixture of8g (0.027 mole) oflO-(2-dimethylaminoethyl)-5-methyl-5H-dibenzo[a,d]-cycloheptene-S-ol and250 ml 2M sulfuric acid is refluxed for 2 hrs. The mixture is cooled inice and made basic by the 1 addition of solid potassium hydroxide. Themixture is extracted with methylene-chloride, the methylenechloride iswashed with water, dried over anhydrous meagnesium sulfate andevaporated in vacuo. The oily residue is distilled at l40C/0.5mm and thedistillate is dissolved in diethylether and treated with gaseoushydrogen chloride. The precipitate is filtered and recrystallized fromdiethylether-ethanol 1:1 to give the product l()-(2-dimethylaminoethyl)5-methylene-5H-dibenzo[a,d]cycloheptenehydrochloride, m.p. l62.5-163C.

EXAMPLE 6 6-trizo[a,d]-cyclohepten -5-one hydrochloride, and startingwith the correspondingly lettered intermediate of step A of thisExample, the following intermediates are obtained,

a. lO-(Z-dimethylaminoethyl)-2,5,7-trimethyl-5H- dibenzo a,d]cyclohepten-5-ol,

l0 2-dimethylam inoethyl )-2,7-dimethoxy-5 methyl-5 H-dibenzo [a,d]cyclohepten 5-ol, c.lO-(2-dimethylaminoethyl)-2,7-dichloro-5-methyI-SH-dibenzo[a,d]cyclohepten-5.-ol, d. 10-( 2-d iisopropylamin oethyl )-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol, or e.lO-(2-dimethylaminoethyl)-5-methyl-2,7-bis(trifluoromethyl)-5H-dibenzo[a,d] cyclohepten-S-ol, respectively. Step C Following the procedure ofExample 6, step C and in place i of 10-( 2-dim ethylaminoethyl)-5-methyl-5H-dibenzo [a,d]-cyclohepten-S-ol, and starting with thecorrespondingly lettered intermediate of step B of this Example, thefollowing products are obtained,

a. 10-( 2-dimethylaminoethyl)-2,7-dimethyl-5-methylene-5H-dibenzo[a,d]cycloheptene hydrochloride, b.10-(2-dimethylaminoethyl)-2-7-dimethoxy-5-methylene-5I-l-dibenzo[a,d]cycloheptene hydrochloride, c. 10-(2-dimethylaminoethyl)-2,7-dichloro-5-methylene-SH-dibenzo[a,d]cycloheptenehydrochloride,

lO-( 2-diisoprop ylaminoethyl )-5-methylene-5 H-dibenzo[a,d]cycloheptene hydrochloride, or

10-(2-dimethylaminoethyl)-2,7-bis(trifluoromethyl)-5-methylene-5H-dibenzo[a,d]cycloheptene hydrochloride, respectively.

EXAMPLES 7 and 8 Tablets and Capsules Suitable for Oral AdministrationTablets and capsules containing the ingredients indicated below may beprepared by conventional techniques and are useful as anti-depressantsat a dose of one tablet or capsule 2 to 4 times a day.

c. 10-(2-dimethylaminoethyl)-2,7-dichloro-5H- dibenzo[a,d]cyclohepten-5-one hydrochloride,

d. 10-( 2-diisopropylaminoethyl)-5H-dibenzo[a,d]cyclohepten -5-onehydrochloride, or

e. l0-(2-dimethylaminoethyl)-2,7-bis(trifluoromethyl)-5H-dibenzo[a,d]cyclohepten -5-one hydrochloride,respectively.

Step B I Following the procedure of Example 6, step B and in the placeof l0-(2-dimethylaminoethyl)-5H-diben- EXAMPLES 9 and 10 SterileSuspension for Injecton and Oral Liquid Suspension The followingpharmaceutical compositions are formulated with the indicated amount ofactive agent using conventional techniques. The injectable suspensionand the oral liquid suspension represent formulations useful as unitdoses and may be administered as anti-depressants. The injectablesuspension is suitable for administration once a day where as the oralliquid suspension is suitably administered 2 to 4 times per day for thispurpose.

Weight (mg) 7 Sterile Oral Ingredients lnjectable Suspension LiquidSuspension 10-(2-dimethylaminoethyl)-10,1 ldihydro-S-methylene5H-dibenzo [a,d]cycloheptene v 25 sodium carboxy methylcellulose U.S.P. 1.25 12.5

methyl cellulose 0.4 I

polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.01

magnesium aluminum silicate 47.5

flavor q.sr

color q.s.

methyl paraben, U.S.P. 4.5

propyl paraben, U.SrPr 1.0

polysorbate 80 (e.g., Tween 80), U.S.P. 5

sorbitol solution, 70%, U.S.P. 2,500

buffer agent to adjust pH for desired stability q.s. q.s.

water for injection, q.s. to 5 ml.

q.s. to 1 ml.

EXAMPLES 11 and 12 Following the disclosure of Examples 7 and 8, and inplace of 10-(2-dimethylaminoethyl)-l0,1l-dihydro-S-methylene-5H-dibenzo[a,d]cycloheptene starting with10-(2-dimethylaminoethyl)-5-methylene SH-dibenzo[a,d]cycloheptene,tablets and capsules may be prepared which are useful asanti-depressants at a dose of one tablet or capsule 2 to 4 times a day.

EXAMPLES l3 and 14 wherein a R and R are independently hydrogen, loweralkyl Following the disclosure of Examples 9 and 10, and having 1 to 3carbon atoms, lower alkoxy having 1 in place ofl0-(2-dimethylaminoethyl)-10,1l-dihydroto 3 carbons atoms, halo havingan atomic weight 5- methylene-5l-l-dibenzo[a,d]cycloheptene starting of19 to 36 or trifluoromethyl,

with l0-(2-dimethylaminoethyl)-5-methylene-5l-l- R and R areindependently lower alkyl having 1 to dibenzo[a,d]cycloheptene,injectable suspensions and 3 carbon atoms. oral liquid suspensions maybe prepared. The injectable 2. A pharmaceutically acceptable acidaddition salt suspension is suitable for administration once a day of acompound of claim 1. whereas the oral liquid suspension is suitablyadminis- 3. The compound of claim 1 which is 10-(2-dimetered 2 to 4times per day for this purpose. thylaminoethyl)-5-methylene-5H-dibenzo[a,d]cy- What is claimed: cloheptene. l. Acompound having the formula

1. A COMPOUND HAVING THE FORMULA
 2. A PHARMACEUTICALLY ACCEPTABLE ACIDADDITION SALT OF A COMPOUND OF CLAIM
 1. 3. The compound of claim 1 whichis 10-(2-dimethylaminoethyl)-5-methylene-5H-dibenzo(a,d)cycloheptene.